In a groundbreaking study that bridges the fields of oncology, epigenetics, and metabolic regulation, researchers from Fudan University and Wenzhou Medical University have unveiled a novel mechanism by which disulfiram, a drug historically prescribed for alcohol dependence, exhibits potent anti-cancer effects in hepatocellular carcinoma (HCC). HCC, a prevalent and lethal liver cancer, often exhibits a complex interplay of dysregulated lipid metabolism and pathological angiogenesis, processes critical to its aggressive growth and poor patient prognosis. This new research sheds light on how disulfiram’s previously unrecognized actions at the molecular level disrupt these pathogenic pathways to inhibit tumor progression.
Central to this discovery is the identification of the RNA methyltransferase TRMT10C as a key mediator of tumor growth in HCC. This enzyme catalyzes methylation modifications on specific RNA molecules, influencing gene expression patterns vital for cancer cell function. The investigative team demonstrated that disulfiram acts as a copper ionophore, facilitating the intracellular influx of copper ions, which in turn downregulates TRMT10C expression. The suppression of TRMT10C induces a cascade of epitranscriptomic changes, notably diminishing methylation on the messenger RNA (mRNA) of the transcription factor c-FOS. This decrease in methylation stabilizes and increases the expression of c-FOS, a crucial regulatory protein with tumor-suppressor properties in this context.
Elevated levels of c-FOS execute a multi-pronged inhibitory effect on the cancer cell microenvironment. It directly represses the expression of PCSK9, a protein intricately involved in lipid metabolism that frequently becomes aberrantly activated in HCC, contributing to excessive lipid droplet accumulation within tumor cells. This accumulation fosters an environment conducive to rapid cancer cell proliferation and survival. Concurrently, c-FOS impedes CD146, a cell adhesion molecule known for its pivotal role in promoting angiogenesis—the formation of new blood vessels—which tumors require for nutrient supply and metastasis.
The functional consequences of modulating this TRMT10C–c-FOS axis were rigorously validated through a series of in vitro and in vivo experiments. Cultured HCC cell lines treated with disulfiram showed marked reductions in lipid droplets and angiogenic markers, while mouse models exhibited significantly slower tumor growth and diminished vascular structures within tumors. Notably, when disulfiram was combined with thalidomide, an established anti-angiogenic agent, these effects were potentiated, providing evidence for possible synergistic therapeutic regimens targeting multiple facets of tumor biology.
Corroborating the translational relevance of these findings, the research team analyzed clinical data sets from HCC patients. This analysis revealed a stark correlation between patient survival outcomes and the expression profiles of the pathway components. High levels of TRMT10C and PCSK9 were statistically linked to a poor prognosis, reinforcing their oncogenic roles. Conversely, patients exhibiting elevated c-FOS expression experienced comparatively prolonged survival, underscoring the potential prognostic and therapeutic value of modulating this pathway.
From a mechanistic viewpoint, the study highlights a novel epigenetic regulation mode within cancer biology through RNA methylation alterations. RNA methyltransferases like TRMT10C are emerging as critical players in orchestrating gene expression beyond the DNA code, influencing mRNA stability, translation efficiency, and protein synthesis. Disulfiram’s ability to target this enzyme and thereby reprogram the epitranscriptome provides an innovative paradigm for repurposing established drugs with known safety profiles while enhancing therapeutic options for difficult-to-treat malignancies such as HCC.
Beyond its molecular insights, this research underscores the broader clinical imperative of addressing metabolic reprogramming and angiogenesis in cancer treatment. Lipid metabolism abnormalities not only confer growth advantages to tumors but also create metabolic vulnerabilities that can be exploited pharmacologically. Meanwhile, angiogenesis remains a proven therapeutic target, and combining agents that interfere with angiogenic signaling with metabolic disruptors, as demonstrated here, may yield substantial synergistic benefits.
The implications of employing disulfiram in HCC are profound. Traditionally utilized to discourage alcohol consumption by inducing unpleasant physiological responses to ethanol, disulfiram’s repositioning as an anti-cancer agent reflects an exciting trend in oncology: drug repurposing. This approach expedites the translation of existing medications with known pharmacokinetics and toxicity profiles into new therapeutic contexts, reducing development times and costs—a critical advantage in the ongoing battle against cancer.
In summary, the multifaceted investigation elucidated how disulfiram orchestrates the downregulation of TRMT10C, leading to enhanced c-FOS activity that suppresses PCSK9-mediated lipid metabolism and CD146-driven angiogenesis, thereby stymying HCC progression. Such discoveries not only illuminate the intricate biological underpinnings of liver cancer but also furnish a viable therapeutic strategy leveraging RNA epigenetics and metabolic intervention. Moving forward, clinical trials will be essential to evaluate disulfiram’s efficacy and safety as a frontline or adjuvant therapy in HCC patients.
The study, published in the reputable journal Science China Life Sciences, marks a significant milestone in oncology research by integrating molecular biology, cancer metabolism, and epigenetics. It exemplifies how detailed mechanistic studies can unveil drug targets and inform precision medicine strategies aimed at improving outcomes for patients afflicted with aggressive malignancies.
Researchers and clinicians alike should note the potential for combinatory regimens involving disulfiram and anti-angiogenic drugs such as thalidomide to maximize anti-tumor efficacy. Moreover, the identification of biomarkers such as TRMT10C, PCSK9, and c-FOS paves the way for more personalized treatment protocols, wherein patient stratification based on molecular signatures could optimize therapeutic responses.
The findings attest to the transformative power of epitranscriptomic modifications in cancer pathogenesis and treatment, encouraging further exploration of RNA-modifying enzymes as drug targets. These insights also spotlight copper ionophores as a class of compounds capable of modulating cancer-related signaling pathways, warranting deeper pharmacological investigations.
By unveiling a previously uncharted molecular pathway linking disulfiram to tumor suppression in liver cancer, this research not only expands the scientific understanding of HCC biology but also catalyzes hope for more effective, accessible, and targeted therapies in the near future.
Subject of Research: Liver cancer (hepatocellular carcinoma), RNA epigenetics, lipid metabolism, angiogenesis, drug repurposing
Article Title: Disulfiram combats hepatocellular carcinoma by modulating TRMT10C-mediated RNA methylation, enhancing c-FOS expression, and suppressing PCSK9 and CD146 to inhibit tumor growth and angiogenesis
News Publication Date: 2024
Web References: http://dx.doi.org/10.1007/s11427-024-2968-1
Image Credits: ©Science China Press
Keywords: hepatocellular carcinoma, disulfiram, TRMT10C, c-FOS, PCSK9, CD146, RNA methylation, lipid metabolism, angiogenesis, anti-cancer therapy, copper ionophore, drug repurposing
Tags: alcoholism drug repurposingangiogenesis and cancer growthc-FOS transcription factor rolecopper ionophore mechanismdisulfiram anti-cancer effectsepitranscriptomics in oncologyhepatocellular carcinoma therapyliver cancer treatment researchmetabolic regulation in cancernovel cancer treatment strategiesRNA methyltransferase TRMT10Ctumor progression inhibition
